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Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo

Lookup NU author(s): Professor Tiago OuteiroORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 The AuthorsA molecular hallmark in Parkinson's disease (PD) pathogenesis are α-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of α-synuclein. Here, we investigated the effects of CDNF on α-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with α-synuclein with a KD = 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils and induces the formation of insoluble phosphorylated α-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with α-synuclein fibrils, though it did not reduce the number of phosphorylated α-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with α-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.

Publication metadata

Author(s): Albert K, Raymundo DP, Panhelainen A, Eesmaa A, Shvachiy L, Araujo GR, Chmielarz P, Yan X, Singh A, Cordeiro Y, Palhano FL, Foguel D, Luk KC, Domanskyi A, Voutilainen MH, Huttunen HJ, Outeiro TF, Saarma M, Almeida MS, Airavaara M

Publication type: Article

Publication status: Published

Journal: Molecular Therapy

Year: 2021

Volume: 29

Issue: 9

Pages: 2821-2840

Print publication date: 01/09/2021

Online publication date: 01/05/2021

Acceptance date: 27/04/2021

Date deposited: 24/08/2023

ISSN (print): 1525-0016

ISSN (electronic): 1525-0024

Publisher: Cell Press


DOI: 10.1016/j.ymthe.2021.04.035

PubMed id: 33940158


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Funder referenceFunder name
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
EXC 2067/1-390729940